What is the process by which protein aggregates interfere with the UPS system?
Well, one clue is that levels of the normal protein ubiquitin are not diminished, and it continues to tag mutant huntingtin for degradation. Thus, it has been suggested that the abnormal proteins clog the other component of the UPS system, the proteasomes. Proteasomes are “master controllers” which normally break down proteins that have been tagged by ubiquitin. Protein aggregates may occupy the proteasomes, inhibiting their normal activity.
Now let’s return to our earlier question: Are huntingtin aggregates a cause or consequence of HD? While the answer remains unclear, the Stanford study concludes that aggregates themselves can contribute to cell toxicity by impairing the UPS system. In a vicious, positive-feedback cycle, the aggregates inhibit the pathway that destroys them. Hence, they continue to build up, resulting in further impairment of UPS function. This accumulation of mutant proteins is gradual, which may explain the late onset of HD.
Future research in this area may focus on how and why the proteasomes shut down in the presence of protein aggregates. Answers to these questions may lead to treatments that can dissolve aggregate proteins or prevent them from forming, if it is proven that they are indeed only harmful.
Last Modified: 05/22/2009
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